Adenosine regulates a wide range of physiological functions through interaction with at least three major classes of adenosine receptors. The A1 and A3 classes of adenosine receptors are inhibitory to adenylate cyclase, while the A2 class is stimulatory to adenylate cyclase. Subclasses of adenosine receptors also occur. Some of these are inhibitory to calcium channels, some are stimulatory to potassium channels, some activate guanylate cyclase, some modulate phospholipid turn-over and some cause smooth muscle relaxation. Possible sites of action of caffeine and theophylline besides blockade of A1-, A2a- and A2b-adenosine receptors remain poorly defined. Inhibition of phosphodiesterase does not seem relevant to the behavioral stimulant activity of caffeine and theophylline, since xanthines that are potent inhibitors of phosphodiesterases are behavioral depressants. Effects on GABAA receptors may account for anxiogenic properties of caffeine, while the relevance of a caffeine-elicited modulation of calcium-release from ryanodine-sensitive intracellular pools, which occurs only at millimolar concentrations of caffeine, is unclear. Caffeine and related xanthines were found to inhibit binding of ligands to the benzodiazepine- and the picrotoxinin-sites on central GABAA receptors. Certain propargyl analogs of caffeine were about 4-fold more potent than caffeine. Remarkably 8-cycloalkyl-1,3-dipropylxanthines enhanced diazepam-binding. Pyrazolopyridines caused stimulation of diazepam-binding, apparently through binding an allosteric site, closely associated with the GABA-site, and inhibition, apparently through direct competition at the benzodiazepine-site. Caffeine and related xanthines enhanced ryanodine-binding to the cyclic ADP ribose-regulated calcium channel associated with muscle sarcoplasmic reticulum. None proved markedly more active than caffeine. Pyrazolopyridines and certain other heterocycles had no effect on ryanodine-binding.